Structural Characteristics of TR3
TR3 (also known as Apo-3, DR3, LARD, Tramp, and WSL-1) is a member of the tumor necrosis factor receptor (TNFR) superfamily of cell-surface antigens. Some members of this superfamily (e.g., NGFR (nerve growth factor receptor), and CD95 (Fas/APO-1)) have broad tissue distribution, while other members of the superfamily (e.g., CD27, CD30, CD40, CD134, 4-1BB, and TR3) are restricted to cells of the lymphoid/hematopoietic system. Except for TR3, this latter group of receptors has been associated with the up-regulation of cell proliferation. TR3 possesses a cytoplasmic death domain homologous to TNFR and CD95 and is thought to be involved in programmed cell death (apoptosis).
Each of these receptors interacts with a cell-surface ligand. In the case of the lymphoid members of this superfamily, the ligands are usually expressed on a complimentary cell type. That is to say, if the receptor is on a T-cell, the ligand is found on an antigen-presenting cell (APC, such as B-cells, macrophages, or dendritic cells) and vice versa. The interaction between these receptor/ligand pairs is thought to deliver signals for activation or death to the receptor bearing cell. To date, the ligand for TR3 has not been discovered.
Role of Activated T-cells in Disease
T lymphocytes are the major cause of graft-versus-host disease (GVHD). Prophylaxis of GVDH is achieved by administering one or more pan T-cell immunosuppressive agents such as cyclosporin, corticosteroids, or methotrexate. These immunosuppressive agents are termed “pan” immunosuppressive agents because they suppress B-cells, T-cells, and the precursor T lymphocytes. It is not uncommon for subjects receiving such immunosuppressive agents to be immunocompromised for three months or more, leaving the subject with <1% normal levels of circulating T-cells. Thus, these agents are associated with significant subject morbidity and mortality due to secondary infection arising from a resulting absence of a functional immune system. Therefore, the development of therapeutic agents that can selectively limit the proliferation of activated T-cells is desirable.
Such therapeutic agents would also be of significant value in halting or at least slowing the progression of other diseases associated with T-cell proliferation, such as, acute and chronic transplantation-rejection diseases (graft-versus-host disease and organ rejection), autoimmune diseases (myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, diabetes, multiple sclerosis, sarcoidosis, myocarditis, thyroiditis and other organ-specific autoimmune diseases), inflammatory diseases (toxic shock syndrome, inflammatory bowel disease and delayed-type hypersensitivity) and cancer (leukemia and lymphoma).
Potential Use of Antibodies to Fas
One proposed therapeutic agent for down-regulating the T-cell immune response was the use of antibodies directed towards Fas (also known as Apo-1 and CD95), a TNFR cell surface protein. Fas is expressed on activated normal human lymphoid cells and lymphoid tumor cells, including B-cells and T-cells, as well as other normal cells. The binding of anti-Fas antibodies to Fas causes growth inhibition and/or apoptosis of cells expressing Fas. Therefore, monoclonal antibodies to Fas were thought to be potentially therapeutically useful for controlling autoimmune diseases, as well as for controlling tumors that express Fas (U.S. Pat. No. 5,891,434 to Krammer, et al., filed Mar. 23, 1995).
Unfortunately, subsequent to the filing of the Krammer et al. patent application, Fas has been found to have a wide tissue distribution which makes it an unlikely candidate for the selective control of the T-cell immune response. Injection of anti-Fas antibodies into wild-type mice caused rapid death of the mice. Autopsies revealed severe damage to the liver by apoptosis. Ogasawara et al., Nature, 364:806–809, 1993.